Bosulif

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Gastrointestinal Toxicity

Diarrhea, nausea, vomiting, and abdominal pain occur with
BOSULIF treatment. Monitor and manage patients using standards of care,
including antidiarrheals, antiemetics, and/or fluid replacement. In the
single-arm Phase ½ clinical trial, the median time to onset for diarrhea (all
grades) was 2 days and the median duration per event was 1 day. Among the
patients who experienced diarrhea, the median number of episodes of diarrhea
per patient during treatment with BOSULIF was 3 (range 1-221). To manage
gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as
necessary [see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS].

Hepatic Toxicity

One case consistent with drug induced liver injury
(defined as concurrent elevations in ALT or AST greater than or equal to 3×ULN
with total bilirubin greater than 2×ULN and alkaline phosphatase less than
2×ULN) occurred in a trial of BOSULIF in combination with letrozole. The
patient recovered fully following discontinuation of BOSULIF. This case
represented 1 out of 1209 patients in BOSULIF clinical trials.

In the 546 patients from the safety population, the
incidence of ALT elevation was 17% and AST elevation was 14 %. Twenty percent
of the patients experienced an increase in either ALT or AST. Most cases of
transaminase elevations occurred early in treatment; of patients who
experienced transaminase elevations of any grade, more than 80% experienced
their first event within the first 3 months. The median time to onset of
increased ALT and AST was 30 and 33 days, respectively, and the median duration
for each was 21 days.

Perform monthly hepatic enzyme tests for the first three
months of treatment with BOSULIF and as clinically indicated. In patients with
transaminase elevations, monitor liver enzymes more frequently. Withhold, dose
reduce, or discontinue BOSULIF as necessary [see DOSAGE AND ADMINISTRATION
and ADVERSE REACTIONS].

Embryofetal Toxicity

There are no adequate and well controlled studies of
BOSULIF in pregnant women. BOSULIF can cause fetal harm when administered to a
pregnant woman. Bosutinib caused embryofetal toxicities in rabbits at maternal
exposures that were greater than the clinical exposure at the recommended
bosutinib dose of 500 mg/day. Females of reproductive potential should be
advised to avoid pregnancy while being treated with BOSULIF. If this drug is
used during pregnancy, or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to the fetus [see Use
in Specific Populations].

Patient Counseling Information

Dosing and Administration Instruct patients to take BOSULIF exactly
as prescribed, not to change their dose or to stop taking BOSULIF unless they
are told to do so by their doctor. If patients miss a dose beyond 12 hours,
they should be advised to take the next scheduled dose at its regular time. A
double dose should not be taken to make up for any missed dose. Advise patients
to take BOSULIF withfood. Patients should be advised: “Do not crush or cut
tablet. Do not touch or handle crushed or broken tablets.”

Gastrointestinal Problems Advise patients that they may experience
diarrhea, nausea, vomiting, abdominal pain, or blood in their stools with
BOSULIF and to seek medical attention promptly for these symptoms.

Low Blood Cell Counts Advise patients of the possibility of
developing low blood cell counts and to immediately report fever, any
suggestion of infection, or signs or symptoms suggestive of bleeding or easy
bruising.

Fluid Retention Advise patients of the possibility of
developing fluid retention (swelling, weight gain, or shortness of breath) and
to seek medical attention promptly if these symptoms arise.

Other Adverse Reactions Advise patients that they may experience
other adverse reactions such as respiratory tract infections, rash, fatigue, loss
of appetite, headache, dizziness, back pain, arthralgia, or pruritus with
BOSULIF and to seek medical attention if symptoms are significant. There is a
possibility of anaphylactic shock.

Pregnancy and Breast-feeding
Advise patients that BOSULIF can cause
fetal harm when administered to a pregnant woman. Advise women of the potential
hazard to the fetus and to avoid becoming pregnant. If BOSULIF is used during
pregnancy, or if the patient becomes pregnant while taking BOSULIF, the patient
should be apprised of the potential hazard to the fetus. Because a potential
risk to the nursing infant cannot be excluded, women that are taking BOSULIF
should not breast-feed or provide breast milk to infants.
Counsel females of reproductive potential to use effective contraceptive
measures to prevent pregnancy during and for at least 30 days after completing
treatment with BOSULIF. Instruct patients to contact their physicians
immediately if they become pregnant during treatment. Advise patients not to
take BOSULIF treatment while pregnant or breastfeeding. If a patient wishes to
restart breastfeeding after treatment, advise her to discuss the appropriate
timing with her physician.

Drug Interactions Advise patients that BOSULIF and certain
other medicines, including over the counter medications or herbal supplements
(such as St. John's wort) can interact with each other and may alter the
effects of BOSULIF [see DOSAGE AND ADMINISTRATION and DRUG
INTERACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 2-year carcinogenicity study was conducted orally in
rats at bosutinib doses up to 25 mg/kg/day in males and 15 mg/kg/day in
females. The exposures achieved at the high dose were approximately 1.5-to
3-fold the human exposure (based on AUC) at the bosutinib dose of 500 mg/day.
The study was negative for carcinogenic findings.

Bosutinib was not mutagenic or clastogenic in a battery
of tests, including the bacteria reverse mutation assay (Ames Test), the in
vitro assay using human peripheral blood lymphocytes and the micronucleus test
in orally treated male mice.

In a rat fertility study, drug-treated males were mated
with untreated females, or untreated males were mated with drug-treated
females. Females were administered the drug from pre-mating through early
embryonic development. The dose of 70 mg/kg/day of bosutinib resulted in
reduced fertility in males as demonstrated by 16% reduction in the number of
pregnancies. There were no lesions in the male reproductive organs at this
dose. This dose of 70 mg/kg/day resulted in exposure (AUC) in male rats
approximately equal to that in humans at the 500 mg/day dose of bosutinib.
Fertility (number of pregnancies) was not affected when female rats were
treated with bosutinib. However, there were increased embryonic resorptions at
greater than or equal to 10 mg/kg/day of bosutinib (40% of the human exposure),
and decreased implantations and reduced number of viable embryos at 30
mg/kg/day of bosutinib (1.4 times the human exposure).

Use In Specific Populations

Pregnancy

Pregnancy Category D

[see WARNINGS AND PRECAUTIONS]

Based on its mechanism of action and findings in animals,
BOSULIF can cause fetal harm when administered to a pregnant woman. Studies in
animals showed reproductive toxicities. If BOSULIF is used during pregnancy, or
if the patient becomes pregnant while taking BOSULIF, the patient should be
apprised of the potential hazard to the fetus.

Fetal exposure to bosutinib-derived radioactivity during
pregnancy was demonstrated in a placental-transfer study in pregnant rats.
Bosutinib was administered orally to pregnant rats during the period of
organogenesis at doses of 1, 3 and 10 mg/kg/day. This study did not expose
pregnant rats to enough bosutinib to fully evaluate adverse outcomes.

In a study conducted in rabbits, bosutinib was
administered orally to pregnant animals during the period of organogenesis at
doses of 3, 10 and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day
of bosutinib, there were fetal anomalies (fused sternebrae, and two fetuses had
various visceral observations), and an approximate 6% decrease in fetal body
weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 4
times those in humans at the 500 mg/day dose of bosutinib.

Nursing Mothers

It is not known whether bosutinib is excreted in human
milk. Bosutinib and/or its metabolites were excreted in the milk of lactating
rats. Radioactivity was present in the plasma of suckling offspring 24 to 48
hours after lactating rats received a single oral dose of radioactive
bosutinib. Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants from BOSULIF, a
decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and efficacy of BOSULIF in patients less than
18 years of age have not been established.

Geriatric Use

In the Phase ½ clinical trial of BOSULIF in patients
with Ph+ CML, 20% were age 65 and over, 4% were 75 and over. No overall
differences in safety or effectiveness were observed between these patients and
younger patients, and other reported clinical experience has not identified
differences in responses between the elderly and younger patients, but greater
sensitivity of some older individuals cannot be ruled out.

Renal Impairment

Reduce the BOSULIF dose in patients with CLcr less than
30 mL/min at baseline. For patients with CLcr 30 to 50 mL who cannot tolerate a
500 mg dose, follow dose adjustment recommendations for toxicity. In a
dedicated renal impairment trial, compared to volunteers with normal renal
function, the exposure (AUC) of bosutinib increased by 60% and 35% in subjects
with CLcr less than 30 mL/min and CLcr 30 to 50 mL/min, respectively [see DOSING
AND ADMINISTRATION and CLINICAL PHARMACOLOGY].